Lecture 15: Target concentration intervention Flashcards
Whats the equation for target concentration?
Target conc = Target effect x C50 / (Emax - Target effect)
What does the ideal dose prediction require?
Individual estimates of Emax, C50, V and CL
What is the initial peak for target conc. dose model?
Loading dose = target conc. x V
What is the average steady state dose model?
Maintenance dose = Target conc. x clearance
What causes PKPD to vary?
Systematic (Predictable)
- Body size
- Disease
- Genotype
Random (not predictable)
- B/w subject variability
- within subject variability
What accounts for most of the CL variability?
Allometry and maturation explains 80% of CL variability
I.e Size and Maturation
If you account for all the obvious features can you standardised clearance?
Substantial variability of clearance remains in each sub population (Weight, sex, age, disease, concomitant medications)
Targeted concentration intervention aims to reduce this
How can smoking reduce the variability? lol In the instance of theophylline use
Theophylline is metabolised by CYP1A2. This enzyme is induced by polycyclic hydrocarbons in fags. Enzyme induction reduces variability because there is a max biological limit on the extent of the enzyme induction
What are the three ways to dose a population?
Population (Same dose for everyone) (some under and overdosed)
Group (Covariate guided, same dose for similar group; i.e same weight, Clcr, genotype)
Individual (Dose determined by individual response, i.e BP, INR, blood conc.)
Reason one of drugs you use for targeted concentration intervention:
- Usefulness is hard to measure (drug is working when the clinical outcome is not easily observable)
- Anti-arrhythmics i.e lignocaine
- Anti-convulsants i.e Phenytoin
- Anti-coagulants i.e warfarin
Example two of drugs you use for targeted concentration intervention:
- Big unpredictable variability (after using weight, renal function etc) and small within subject variability
- > Too much variability means either inadequate beneficial effect or too much adverse effect
- > Observing patient response can predict future dose needs
What are the steps for the target concentration strategy?
- Choose target conc.
- Determine V and Cl using Wt etc
- Calculate LD and MD rate
- Measure response (Revise target conc.)
- Measure concs. (Revise V and CL)
Aiming to achieve the best individual dose.
Are target concentrations and target effects well known for drugs?
Target concentrations and PK parameters are known for most medicines which are helped by TCI
The pharmacodynamic parameters for medicines that use TCI are typically not well known. Reflects difficulty of measuring a response.
Whats the rational for measuring drug concentrations and what are some things to consider:
- > Number of samples (1 for most meds, 2 for gentamicin)
- > Timing of samples, most medicines = middle of dosing interval, gentamicin ‘peak’ and ‘trough’
Rational approach to measuring drug concentration is based on using the measurement to predict Pk parameters i.e CL. Timing of measuring is mid dose, unless you pair a peak and a trough.
Why measure in the middle of the dosing interval?
Will be closer to the average steady state
